Submission Details

LAMC3 was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2011 (21572417: O'Roak et al. 2011). Over 25 unique variants have been reported in humans. Autism spectrum disorder was the primary ascertainment for the largest number of individuals, but variants have also been reported in probands with intellectual disability and/or developmental delay as well. The variants were primarily identified in individuals with limited phenotype data from large cohort studies, and none had experimental evidence of gene impact (21572417: O'Roak et al. 2011; 23160955: O’Roak et al. 2012; 27525107: Yuen et al. 2016; 28965761: Turner et al. 2017; 28191889: Stessman et al. 2017; 30564305: Guo et al. 2018; 31398340: Ruzzo et al. 2019). Recent large-scale case-control studies also failed to identify a significant association between variation in the gene and autism spectrum disorder (31398340: Ruzzo et al. 2019; 31981491: Satterstrom et al. 2020). A potential mechanism of disease has not been delineated, and no experimental data were identified that provided specific support for this gene-disease relationship. In summary, there is convincing evidence disputing the relationship between LAMC3 and autosomal dominant complex neurodevelopmental disorder. More evidence is needed to either support or refute the role LAMC3 plays in this disease. This classification was approved by the Intellectual Disability and Autism Gene Curation Expert Panel on 09/01/2020. The relationship of the LAMC3 gene with an autosomal recessive cortical malformation phenotype will be addressed separately.

LAMC3 was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2011 (O'Roak et al., PMID: 21572417). Over 25 unique variants have been reported in humans. Autism spectrum disorder was the primary ascertainment for the largest number of individuals, but variants have also been reported in probands with intellectual disability and/or developmental delay. The variants were primarily identified in individuals with limited phenotype data from large cohort studies, and none had experimental evidence of gene impact (PMIDs: 21572417, 23160955, 27525107, 28191889, 28965761, 30564305, 31398340). Recent large-scale case-control studies also failed to identify a significant association between variation in the gene and autism spectrum disorder (PMIDs: 31398340, 31981491). A potential mechanism of disease has not been delineated, and no experimental data were identified that provided specific support for this gene-disease relationship.

In summary, the evidence supporting the relationship between LAMC3 and autosomal dominant complex neurodevelopmental disorder has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role LAMC3 plays in this disease. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on September 1, 2020 (SOP Version 7). The relationship of the LAMC3 gene with an autosomal recessive cortical malformation phenotype will be addressed separately.